1. Field of Invention
Dopaminergic, anticataleptic central nervous system compositions useful in the treatment of central nervous system ailments and disorders, particularly Parkison's disease, depressions, spasticity, hyperkinesis, and rigidity. Treatment of such central nervous system disorders or ailments with combination therapy including a 1,3-dimethyl-5-aminodamantane compound.
2. Prior Art
In the past, numerous proposals have been made for drugs which influence the central nervous system and are useful for the treatment of ailments or disorders thereof, particularly including Parkinson's disease, depressions, spasticity, hyperkinesis, rigidity, and the like. At present, such treatment is predominantly carried out with the employment of three separate therapeutically active agents, having different modes of action and having widely different structures. These products are L-dopa, aminoadamantanes, and anticholinergics. Dependent on the form and intensity of the disease involved, rigor, tremor, and bradyphrenia are the target of the treatment. In many cases, however, single doses of 200 to 300 milligrams of the active agent are necessary to achieve a satisfactory effect on rigidity, but such dosages are already regarded as undesirably pathological. Such drugs act on akinesia and rigidity, but a wide range of effects, including also desirable reduction of tremor and treatment of bradyphrenia, can in most cases only be effected through the employment of greatly increased dosages. It is therefore obviously necessary to provide new active ingredients or agents or combinations thereof, whereby the desirable effects can be accomplished without the undesirable and even pathological increase in dosage. It is therefore highly desirable to provide combinations of active agents which potentiate each other, or in which one potentiates the activity of the other, both of which active agents are preferably already known and established in therapy. At the same time, any such combination should present, if at all possible, an improved therapeutic ratio and diminished side effects. This is sometimes possible when the potentiating effect of the one active ingredient upon the other is sufficient to permit a significant reduction in dosage.
Among the substances previously proposed for influencing the central nervous system and as especially useful in the treatment of hyperkinesis and rigidity, and particularly in the treatment of Parkinson's disease, is the compound 1,3-dimethyl-5-aminoadamantane or a pharmaceutically-acceptable salt thereof, which acts upon rigor, tremor, and akinesia. Animal experiments have revealed the anticataleptic and locomotor activity of this compound at doses of five through twenty milligrams per kilogram of body weight.
Many recent publications have dealt with the range of activity of 1,3-dimethyl-5-aminoadamantane and its pharmaceutically-acceptable salts, e.g.:
Drugs of the Future Vol. I, No. 9 (1976), 427 ff; Arzneimittel-Forschung "Drug Research" 27 (II), No. 7 (1977), 1477-1487 ff; European Journal of Pharmacology 26 (1974), 9-14, North-Holland Publishing Company; Arzneimittel-Forschung "Drug Research" 23, No. 12 (1973), 1737-1739. See also U.S. Pat. No. 4,122,193, issued Oct. 24, 1978, claiming compositions of 1,3-dimethyl-5-aminoadamantane and pharmaceutically-acceptable salts thereof and a method of treating hyperkinesis therewith.
The second active ingredient, which also plays an important part in the unpredictable effectiveness of the new combinations and method of the present invention, is a methylxanthine compound, e.g., caffeine or theophylline, both of which are old and well-known in the art and the therapeutic action of which is sufficiently described in the literature.
With regard to the prior art concerning potentiation of dopaminergic activity by means of drug combinations and combination therapy, reference is made herein to German OL No. 2518677, filed Apr. 26, 1975, and laid open on Nov. 20, 1975, which discloses dopaminergic stimulating compositions comprising certain alkaloids together with phosphodiesterase inhibitors. Although caffeine and theophyllamine are reported to be phosphodiesterase inhibitors, any potentiation which might result from a combination thereof with certain alkaloids certainly is no teaching or suggestion that they might be used to potentiate the activity of 1,3-dimethyl-5-aminoadamantane or a pharmaceutically-acceptable salt thereof, which indeed possess a far different chemical structure and activity than the alkaloids of the German OL.
As far as combination therapy, reference is also made to U.S. Pat. No. 3,961,060, issued June 1, 1976, wherein a phosphodiesterase inhibitor such as caffeine is combined with dopa, m-tyrosine, apomorphine, or a compound designated ET495, for purposes of allegedly potentiating dopaminergic effect. All the compounds disclosed in that patent, the dopaminergic activity of which is allegedly potentiated, have structures far different than the 1,3-dimethyl-5-aminoadamantane employed in the compositions and method of the present invention, and of course are also presumed to operate along entirely different metabolic pathways. Further, the evidence apparently presented in the U.S. Pat. No. 3,961,060 appears to be limited to potentiation of the dopaminergic effect of dopa itself by caffeine, which of course is hardly any suggestion to combine a methylxanthine such as caffeine or theophylline with a compound such as 1,3-dimethyl-5-aminoadamantane or a pharmaceutically-acceptable salt thereof, inasmuch as such compound contains three (3) rings compared to the single ring in dopa, as well as three (3) less functional groups than dopa, much less that caffeine or theophylline or any methylxanthine compound would in fact serve to potentiate the highly desirable activity of 1,3-dimethyl-5-aminoadamantane or a pharmaceutically-acceptable salt thereof, particularly with respect to what is undoubtedly the most important result of such combination therapy, namely, reduction in rigidity.
Accordingly, in the compositions of the present invention and according to the method of the present invention, the methylxanthine compound such as caffeine or theophylline unpredictably, and to an unpredictable and highly desirable extent, potentiates the activity of the 1,3-dimethyl-5-aminoadamantane or pharmaceutically-acceptable salt thereof and provides another important addition to the physician's armamentarium of useful drugs in this area.